Targeting purinergic signaling and MTAP-associated metabolism in cancer: A functional immunometabolic convergence...

Area of Science:

• Cancer Biology
• Immunology
• Metabolic Reprogramming

Background:

• Cancer progression involves metabolic changes and immune evasion.
• Extracellular adenosine (eADO) metabolism, primarily via CD73, drives adenosine receptor activation (A2AR, A2BR) in the tumor microenvironment (TME), suppressing anti-tumor immunity and immunotherapy response.
• MTAP deletion, often with CDKN2A loss, alters methylation homeostasis and creates metabolic dependencies (PRMT5, MAT2A) without increasing eADO.
• Nucleoside transporters, such as ENT1, regulate intracellular adenosine (iADO) in T cells, linking purinergic signaling to intracellular immunometabolism.

Purpose of the Study:

• To propose a framework for understanding the convergence of extracellular and intracellular metabolic pathways in regulating tumor immune escape.
• To elucidate the roles of CD73-mediated eADO signaling, ENT1-mediated iADO handling, and MTAP loss-associated metabolic rewiring in cancer immunity.

Main Methods:

• Review and synthesis of existing literature on cancer metabolism, purinergic signaling, and tumor immunology.
• Analysis of the interplay between CD73, MTAP, and ENT1 in the context of the tumor microenvironment.
• Conceptual framework development integrating extracellular and intracellular metabolic regulation of immune responses.

Main Results:

• CD73-driven eADO signaling suppresses anti-tumor immunity through adenosine receptors.
• MTAP deletion leads to metabolic rewiring and dependencies impacting cancer cells, but not directly increasing eADO.
• ENT1 regulates intracellular adenosine availability in T cells, adding another layer to immunometabolic control.
• These pathways (CD73, MTAP, ENT1) function cooperatively to promote tumor immune escape.

Conclusions:

• A functional immunometabolic convergence framework explains how CD73, ENT1, and MTAP loss collectively stabilize tumor immune escape.
• Targeting these metabolic pathways offers potential strategies for enhancing anti-tumor immunity and immunotherapy efficacy.